Mechanisms and clinical relevance of TRAIL‐triggered responses in the synovial fibroblasts of patients with rheumatoid arthritis

Objective Results of studies in mice suggest a protective role for TRAIL in arthritis. The aim of this study was to investigate the role of TRAIL in patients with rheumatoid arthritis (RA). Methods In the present study, we compared RA fibroblast‐like synoviocytes (FLS) that were resistant or sensitive to TRAIL‐induced apoptosis and the expression of TRAIL receptors in these cells, and also investigated the clinical features of the patients from whom the FLS were derived. Furthermore, we evaluated the levels of TRAIL and its soluble decoy receptor osteoprotegerin (OPG) in patients with RA, patients with osteoarthritis (OA), and patients with spondylarthritis (SpA). Results Sensitivity to TRAIL‐induced apoptosis varied in FLS from different patients, and the severity of disease in patients with RA was inversely correlated with the susceptibility of their FLS to TRAIL‐induced apoptosis. TRAIL‐sensitive cells expressed significantly lower levels of TRAILR‐1, and silencing of TRAILR‐1 increased TRAIL‐induced apoptosis in RA FLS. TRAIL levels were elevated in the arthritic joints of patients with established RA, and TRAIL levels in the synovial fluid of these patients were elevated compared with levels in the synovial fluid of patients with OA or SpA. At baseline, a low OPG‐to‐TRAIL ratio in the sera of patients with early RA was associated with a better evolution of disease activity, but high serum levels of TRAIL at followup were associated with joint damage. Conclusion These findings suggest that TRAIL has a dual role in RA, and that the resistance of RA FLS to TRAIL‐induced apoptosis is associated with a disease‐promoting activity of TRAIL in RA.